Abstract
The tumor microenvironment plays a pillar role in the progression and the distance dissemination of cancer cells in the main malignancies affecting women—epithelial ovarian cancer, endometrial cancer and cervical cancer. Their milieu acquires specific properties thanks to intense crosstalk between stromal and cancer cells, leading to a vicious circle. Fibroblasts, pericytes, lymphocytes and tumor associated-macrophages orchestrate most of the biological pathways. In epithelial ovarian cancer, high rates of activated pericytes determine a poorer prognosis, defining a common signature promoting ovarian cancer proliferation, local invasion and distant spread. Mesenchymal cells also release chemokines and cytokines under hormonal influence, such as estrogens that drive most of the endometrial cancers. Interestingly, the architecture of the cervical cancer milieu is shaped by the synergy of high-risk Human Papilloma Virus oncoproteins and the activity of stromal estrogen receptor α. Lymphocytes represent a shield against cancer cells but some cell subpopulation could lead to immunosuppression, tumor growth and dissemination. Cytotoxic tumor infiltrating lymphocytes can be eluded by over-adapted cancer cells in a scenario of immune-tolerance driven by T-regulatory cells. Therefore, the tumor microenvironment has a high translational potential offering many targets for biological and immunological therapies.
Highlights
The tumor microenvironment plays a pillar role in the invasion, progression and subsequent dissemination of cancer cells
In Epithelial Ovarian Cancer (EOC) malignant cells are associated with many other different ancillary cells that are present within the reactive stroma—namely pericytes, adipocytes, endothelial cells, fibroblasts and myofibroblasts, bone-marrow-derived mesenchymal stem cells (BM-MSCs), mesothelial cells and leucocytes [1,2,3]
The cancer cells enable stromal ones to up-regulate CCL20 thanks to the paracrine trigger of the molecular cascade by the activation of the transcription factor CCAAT enhancer binding protein beta (C/EBPβ) and to the release of IL6 [10]. The latter has a wide range of functions: firstly, it acts as a chronic pro-inflammatory/pro-tumoral agent via the chemoattraction of T-helper 17 (Th17); secondly, it can be considered a disruptor of APCs helping cancer cells in immunity escape and a cancer promoter thanks to the induction of matrix metalloproteinase 9 (MMP-9) [10]
Summary
The tumor microenvironment plays a pillar role in the invasion, progression and subsequent dissemination of cancer cells. The genetic expression cluster of reactive stromal signature, described by the Australian Ovarian Cancer Study Group (AOCS), predicts a poorer prognosis and correlates with high levels of desmoplasia and Alpha Smooth Muscle Actin (αSMA) expression by tumor-associated myofibroblasts and pericytes [3,4]. Considering the endometrium, the stromal population around the endometrial glands is characterized by a critical juxtacrine and paracrine activity of estrogen receptor α (ERα), encoded by the gene ESR1, which mediates the release of various growth-factors and cell-cycle-related proteins This hormonal influence can be enhanced by the dysregulation of other pathways such as E-cadherin loss and mutations of β-catenin, orchestrating in some cases an epithelial-mesenchymal transition (EMT) during carcinogenesis [5,6,7]. This evidence might lead by the near future to the application of target therapies and immunological treatments that will focus on the peculiar biological signature characterizing the cancer cells and their vital microenvironment
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